Fibrinogen, a critical component of blood coagulation, extravasates across a damaged blood-brain barrier (BBB) and accumulates as fibrin deposits at specific sites of injury. The widespread deposition of fibrin within the nervous system is well documented in demyelinating plaques in Multiple Sclerosis (MS). Our published work pioneered studies of fibrinogen in CNS disease. We identified fibrinogen as a novel molecular link between BBB disruption and inflammatory demyelination. We demonstrated novel cellular functions of fibrinogen as an activator of microglia via interaction with the CD11b/CD18 integrin. Given that fibrin and its cell surface receptors play a role in both the inflammatory response in the CNS and tissue remodeling/repair, they are prime candidates to be critical determinants of inflammatory demyelination. Our ultimate goal is to design novel therapeutic approaches to specifically target the proinflammatory functions of fibrin in the CNS with potential application in MS and other neurologic diseases associated with fibrin deposition. In this grant renewal application we employ a multifaceted experimental design to determine the role of fibrinogen in T cell trafficking in the CNS using state-of-the-art in vivo two-photon microscopy (Aim 1), the mechanisms of fibrinogen/CD11b signaling in T cell immune modulation and epitope spreading using genetic models of fibrinogen depletion or specific inhibition of its interactions with its receptors in viv (Aim 2), the pathways downstream of fibrinogen/CD11b/CD18 signaling involved in the activation of the innate and adaptive immune responses in the CNS (Aim 3), and the therapeutic potential in neuroinflammatory disease of two novel inhibitors developed in our laboratory that specifically target the interaction of fibrinogen with CD11b/CD18 without adverse effects in blood coagulation (Aim 4). The proposed studies will provide a cellular and molecular definition of the role of hemostatic factors in the pathogenesis of inflammatory demyelination and will determine the therapeutic efficacy of novel inhibitors of fibrinogen function in neuroinflammation. Identifying the mechanisms of fibrin actions in the nervous system could ultimately illuminate new therapeutic strategies for the treatment of MS.